1. Field of the Invention
This invention relates to 5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepines containing an .omega.-(dimethylamino)alkyl or .omega.-(pyrrolidino)alkyl substituent on the ring nitrogen, and optionally containing substituents in the 5-phenyl ring and/or the 6-, 7-, 8- or 9-position, and their nontoxic pharmaceutically acceptable acid addition salts, which are useful as analgesic and/or antitussive agents.
2. Description of the Prior Art
In the Journal of Pharmaceutical Sciences, 58, 1460-1463 (1969), H. A. Luts discloses substituted 1,4-benzoxazepines of the formulae ##STR2## No specific utility is given for the compounds, it is merely stated that they were prepared "in a search for new compounds with central nervous system activity". Several of the intermediate compounds are the same as certain intermediates in the present application, and are prepared by the same or similar processes. The right-hand compound above is itself an intermediate in the preparation of certain of the final products claimed herein.
G. N. Walker et al., in the Journal of Organic Chemistry, 36, 305-8 (1971), disclose inter alia substituted 2,3,4,5-tetrahydro-1,4-benzoxazepines of the formulae ##STR3## These compounds are described as having "only moderate hypotensive (and no significant central nervous) effects". They were prepared by methods different from those utilized in the present application.
Chemical Abstracts, 73, 120697h (1970) reports that German OLS 2,014,223 describes ##STR4## and the corresponding 2,3-dihydro compound as being tranquilizers, hypnotics and muscle relaxants. As indicated above, this compound is an intermediate in the preparation of certain of the final products claimed herein.
German OLS 2,100,654 discloses, inter alia, substituted 2,3-dihydro-1,4-benzoxazepines of the formula ##STR5## in which the fused benzene ring A may contain "one or more same or different substituents", R.sup.1 may be inter alia substituted or unsubstituted phenyl and R.sup.3, R.sup.4, R.sup.5 and R.sup.6 may be hydrogen or any of a wide variety of substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl or heterocyclyl substituents. Also disclosed are acid addition salts and quaternary ammonium salts of the above compounds, having the formula ##STR6## in which A, R.sup.1, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are the same as above, Z.crclbar. is an anion and R.sup.2 is hydrogen or an alkyl or aralkyl radical. The only R.sup.2 group which is exemplified is methyl.
Belgian Patent 764,865 discloses, inter alia, substituted 2,3,4,5-tetrahydro-1,4-benzoxazepines of the formula ##STR7## in which the combination of R.sup.1 and R.sup.7 may be inter alia substituted or unsubstituted phenyl provided that at least one of R.sup.2, R.sup.3, R.sup.4, R.sup.5 or R.sup.6 is other than hydrogen, and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and A are as set forth in the preceding paragraph relating to OLS 2,100,654.
South African patent 67/05136 describes 1,3-disubstituted pyrrolidines of the formula ##STR8## having tranquilizing and/or analgetic activity, in which inter alia AZ may be ##STR9## wherein R.sup.4 is H, (lower)alkyl, (lower)alkoxy, trifluoromethyl, halogen of molecular weight less than 80 or di(lower)alkylamino. Specifically disclosed 4-(3-pyrrolidinyl)-2,3,4,5-tetrahydro-1,4,-benzoxazepines utilized as intermediates include compounds of the formula ##STR10## in which R.sup.4 is hydrogen, 9-methoxy or 8-diethylamino. No pharmaceutical activity is ascribed to these intermediates and the intermediates do not include 5-phenyl substitution or any 4-substituents other than the 4-(3-pyrrolidinyl) moiety.
In the Journal of the Chemical Society, 1137-1141 (1965), D. Huckle et al. describe inter alia compounds of the formula ##STR11## in which R may be 2-(dimethylamino)ethyl, 2-(pyrrolidino)ethyl, 2-(piperidino)ethyl, 2-(morpholino)ethyl, 3-(dimethylamino)propyl or 3-(morpholino)propyl. Where R is 2-(morpholino)ethyl, the compound may also contain a 9-methyl, 9-methoxy or 7-methoxy substituent. The compound ##STR12## also is disclosed. No pharmaceutical activity is ascribed to any of the compounds, No 5-substituent other than oxo is disclosed.
U.S. Pat. No. 2,807,628 discloses compounds of the formula ##STR13## in which R is H, chloro, fluoro, (lower)alkyl, (lower)alkoxy or monocyclic alkyl, R.sup.1 is H, alkyl or aryl, R.sup.2 is H or methyl and R.sup.3 is .beta.-chloro(lower)alkyl. The compounds are described as adrenergic blocking agents, anticholinergic agents, adrenolytic agents and/or antihistamines.
U.S. Pat. No. 3,346,565 describes substituted 1,2,3,4,5-tetrahydro-4,1-benzoxazepines of the formula ##STR14## in which R is H or halogen, R.sup.1 is alkyl, aralkyl, acyl or ##STR15## in which n is 1-5 and R.sup.3 and R.sup.4 are H, alkyl or, taken together with the nitrogen, may represent an optionally substituted heterocyclic ring, R.sup.2 is H, alkyl, aryl or aralkyl, and X is O or H.sub.2. Of the specifically disclosed compounds in which R.sup.1 is ##STR16## X is in each instance oxygen. It is to be noted that these compounds are 1,2,3,5-tetrahydro-4,1-benzoxazepines rather than the 2,3,4,5-tetrahydro-1,4-benzoxazepines claimed in the present application. Thus, in these prior art compounds, the ring nitrogen is immediately adjacent the fused benzene ring (rather than being further removed via an intervening carbon atom, as in the present invention) and the ring oxygen is separated from the fused benzene ring via an intervening carbon atom (rather than being immediately adjacent, as in the present invention). These differences sufficiently change the chemical character of the ring nitrogen atom, for example, so that the compounds of the present invention cannot be prepared by the process described in U.S. Pat. No. 3,346,565. Thus, that patent states that the R.sup.1 substitutent is introduced by a "conventional" method, e.g. by reacting the compound of the formula ##STR17## However, it has been found that the intermediates of the present invention, e.g. those of the formula ##STR18## where R.sup.3 is H or Cl do not react with compounds such as ##STR19## in which n is 2 or 3; only starting material was recovered.
U.S. Pat. No. 3,676,460 discloses compounds of the formula ##STR20## in which X.sup.1 and X.sup.2 are H, halogen, (lower)alkyl or (lower)alkoxy, which are stated to have strong central nervous system activity. None of these compounds have a substituent on the ring nitrogen.
U.S. Pat. No. 3,686,217 discloses compounds of the formula ##STR21## in which R is H, halogen, (lower)alkyl, (lower)alkoxy, trifluoromethyl or the like, R.sup.2 is H or (lower)alkyl and R.sup.1 is "a hydrocarbon radical of aliphatic character" (more particularly stated to be alkyl, alkenyl, cycloalkyl or phenylalkyl). The compounds are stated to have pronounced action on the central nervous system and to be useful as analgesics, psychotropic agents, anti-aggression agents, etc. One of the disclosed methods of preparing the above compounds is by reduction of a compound of the formula ##STR22## in which R.sup.1' --CH.sub.2 -- has the same meaning as R.sup.1 with lithium aluminum hydride. However, all of these prior art compounds contain a 2-phenyl substituent not found in the instantly claimed compounds and do not contain the 5-phenyl substituent of the instantly claimed compounds. Further, the R.sup.1 substituents do not resemble or suggest the .omega.-(dimethylamino)alkyl or .omega.-(pyrrolidino)alkyl substituents of the instantly claimed compounds.
U.S. Pat. No. 3,794,639 discloses, inter alia, compounds of the formula ##STR23## in which X may be H, halogen (lower)alkyl, (lower)alkoxy, amino, nitro, trifluoromethyl, etc., R.sup.2 and R.sup.3 are H or, taken together, may be O, and R.sup.1 may be inter alia --AB in which A is a (lower)alkylene group and B is a basic N-containing radical of less than 12 carbon atoms. The R.sup.1 group is introduced by reacting the desired 1,4-benzoxazepin-5-one with either (1) BA-halogen or (2) halogen-A-halogen and subsequent reaction of the intermediate product with H-B. To obtain compounds in which R.sup.2 and R.sup.3 are H, the 5-oxo group is subsequently reduced with LiAlH.sub.4. Of the 21 examples in the patent, 20 describe the preparation of benzothiazepines and only one deals with a benzoxazepine; it discloses 7-methoxy-3,4-dihydro-2-furyl-2H-1,4-benzoxazepin-5-one. It is to be noted that all compounds disclosed therein contain a 2-aryl substituent (not present in the instantly claimed compounds) and do not contain a 5-phenyl substituent as in the instantly claimed compounds. The compounds are stated to have CNS modifying activity and to be useful as tranquilizers.
Derwent Abstract 39846F indicates that Dutch Patent No. 69.04326 discloses 3-aryl-4-(disubstituted aminoalkyl)-1,4-benzoxazepin-5-(4H)-ones having anti-inflammatory and analgesic activity. Specifically disclosed is the compound of the formula ##STR24## These compounds are not tetrahydro, cannot contain a 5-phenyl substituent, and do contain 3-phenyl and 5-oxo substituents not contained in the instantly claimed compounds.